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    • "Additionally, lamotrigine differentially alters basal and stimulated extracellular 5-HT concentration in the hippocampus of rats using microdialysis [Ahmad et al., 2004, 2005] and decreases platelet 5-HT concentration in patients with bipolar disorder [Sagud et al., 2008]. These studies suggest that lamotrigine inhibits 5-HT uptake, and thus that its mode of action may resemble that of the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs, by increasing the amount of serotonin in the synapse [Sagud et al., 2008]. Serotonin is a biogenic monoamine and an important neurotransmitter/neuromodulator in the peripheral and central nervous system, where it plays a role in behavioral functions including mood [Veenstra-VanderWeele et al., 2000; Mohammad-Zadeh et al., 2008]. "
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    ABSTRACT: Lamotrigine, a mood stabilizer used clinically in the treatment of bipolar disorder, is thought to exert actions on the serotonin system. However lamotrigine's exact mechanism of action remains unclear. The current study investigated whether lamotrigine might exert its effects through altering the expression of the serotonin transporter (5-HTT) gene and its regulatory transcription factors Y box binding protein 1 (YB-1) and CCCTC-binding factor (CTCF). We further considered whether functional variable number tandem repeat (VNTR) polymorphisms in the promoter region of 5-HTT, (5-HTTLPR) and within intron 2 (Stin2) of the gene, moderated any putative gene expression changes. The study employed an in vitro design carried out in human lymphoblastoid cell lines (LCLs) to investigate the effects of lamotrigine treatment at 0.04, 0.2, and 0.4 mM doses for 24 hr on the mRNA expression of 5-HTT, YB-1, and CTCF. LCLs were selected based on combinations of haplotypes of the two VNTRs in the serotonin transporter gene; creating low-expressing and high-expressing LCL groups. Ubiquitin C (UBC) and topoisomerase I (TOP1) genes were found to be the most stably expressed housekeeping genes in drug-treated LCLs. Subsequently, quantitative PCR revealed that higher doses of lamotrigine significantly lowered 5-HTT expression and increased CTCF expression. Haplotype-specific differences in CTCF expression were found in response to lamotrigine, with strongest expression changes observed in the high-expressing LCLs. These data provide an allele-specific in vitro model for examining the molecular targets of lamotrigine, and support the important role of the serotonin transporter gene in its clinical mechanism of action. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2013; 162(5). DOI:10.1002/ajmg.b.32178 · 3.27 Impact Factor
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    ABSTRACT: Rationale Although antipsychotic drugs are prescribed for the treatment of schizophrenia and psychotic disorders, some of these drugs are also reported to possess antidepressant properties. Therefore, they are more frequently used either as a monotherapy or as an addition to antidepressant medication treatment in depression. Objectives The data on the effects of antipsychotic drugs on serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) in vivo when given to patients in therapeutic doses are still scarce. Methods Patients with schizophrenia or schizoaffective disorders in both male and female patients, were treated with antipsychotic drugs: 25 patients received olanzapine (12.8 ± 2.8 mg/day), 14 patients were treated with typical antipsychotic, fluphenazine N=14 (10.5 ± 2.5 mg/day) and for comparison, 21 patients were treated with ziprasidone (109.0 ± 27.1 mg/day). Platelet 5-HT concentration was determined fluorimetrically and evaluated at baseline and after 28 days in 65 healthy control subjects and in 60 patients. Results Platelet 5-HT concentration did not differ significantly [F(3, 246)=0.597; p=0.677] between medicationfree healthy control subjects sampled at baseline and after 28 days compared to schizophrenic patients sampled before and 28 days after antipsychotics. Tukey’s multiple comparison test revealed that treatment with fluphenazine (p=0.853), olanzapine (p=0.117), or ziprasidone (p=1.000) did not significantly alter platelet 5-HT concentration after 28 days of treatment compared to their baseline values, i.e. values before treatment. Conclusions Although all antipsychotics used in the study possess some antidepressant effects that are assumed to be related to their serotonergic properties, and have been reported to have in vitro binding affinity for human 5-HTT, the present study failed to detect significant in vivo effects of typical (fluphenazine) or atypical (olanzapine, ziprasidone) antipsychotics on platelet 5-HT concentration in schizophrenic patients.
    03/2012; 3(1). DOI:10.2478/s13380-012-0001-5
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    ABSTRACT: Introduction. Lamotrigine is a phenyltriazine compound that inhibits voltage-gated sodium channels, decreasing release of glutamate and aspartate, and inhibits serotonin, norepinephrine and dopamine reuptake. Reports of toxicity in the literature are limited to case reports and primarily involve coingestants. This case series is intended to report the clinical manifestations of lamotrigine toxicity. Methods. This retrospective case series from 2003 to 2012 studies the effects of lamotrigine toxicity when not confounded by coingestants. Admission records at an inpatient toxicology center were reviewed for lamotrigine-only exposure based on history with supporting laboratory data when available. After identification, these charts were reviewed again to characterize vital signs, neurological examination findings, specific laboratory and electrocardiography parameters, and complications. Results. Fifty-seven patients were identified with possible lamotrigine toxicity. Nine patients, including three toddlers, had lamotrigine-only ingestions. Three of these patients had seizures, four were hypertensive, five were tachycardic, and four experienced tachypnea. Mental status was altered in all nine (depressed (n = 4), agitated (n = 5) or both (n = 3)). Five patients were hyperreflexic and experienced intermittent myoclonus, and two had inducible clonus. On electrocardiogram, two patients experienced QRS prolongation (114-116 ms), and four had QTc prolongation (463-586 ms). No patient had life-threatening symptoms or signs. Serum levels of lamotrigine were available in seven patients, and averaged 35.4 mg/L (17-90 mg/L). The therapeutic range for sLTG is 3-14 mg/L. Conclusions. Lamotrigine toxicity manifested with minor-moderate neurologic and/or electrocardiographic effects. Toxicity reflects the known pharmacologic actions of lamotrigine: serotonin, norepinephrine and dopamine reuptake inhibition, and sodium channel blockade.
    Clinical Toxicology 07/2013; 51(7). DOI:10.3109/15563650.2013.818685 · 3.12 Impact Factor